Resolution of the non steroidal antiandrogen 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide and the determination of the absolute configuration of the active enantiomer

Abstract

The nonsteroidal antiandrogen 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2- hydroxy-2-methyl-3'-(trifluoromethyl)-propionanilide (1) (ICI 176334) has been resolved by chromatographic separation of the diastereomeric (R)-camphanyl esters of the precursor thioether 2 followed by hydrolysis and oxidation of the isolated enantiomers. In addition, an asymmetric synthesis of (S)-3-bromo-2-hydroxy-2-methylpropanoic acid (11) and subsequent conversion into the (S)-sulfone 6a has established that the more potent enantiomer of 1 has the R absolute configuration.

Characterization of In Vitro Synthesized Equine Metabolites of the Selective Androgen Receptor Modulators S24 and S4

“…The substrates S24 and S4 (see Fig.1) for the in vitro assays were prepared using in-house chemical synthesis according to procedures published elsewhere [12][13][14][15]. Nicotinamide adenine dinucleotide phosphate (NADPH) was purchased from Roche Diagnostics (Mannheim, Germany); uridine 5 0 -diphosphoglucoronic acid (UDPGA) and D-saccharic acid 1,4-lactone were purchased from Sigma (St. Louis, MA); and adenosine 3 0 -phosphate 5 0 -phosphosulfate (PAPS) was purchased from Calbiochem/EMD Biosciences Inc. (La Jolla, CA).…”

Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety

“…[8][9][10][11][12] Reagents and conditions: All newly synthesised compounds were evaluated for their antiproliferative effect in an in vitro 2D monolayer assay using four human prostate cancer cell lines ( Table 1, absolute IC50 in µM). LNCaP, 5 VCaP and 22Rv1 cell lines exhibit some androgen sensitivity, whereas DU-145 is hormone-insensitive (Supporting Information, section S.3).…”

“…All planned modifications were carried out according to an optimised three or four-step synthetic pathway, adapted from literature procedures, [8][9][10][11][12][13][14] summarised in Schemes 1 and…”

Selective Androgen Receptor Modulators in Drug Discovery: Medicinal Chemistry and Therapeutic Potential

“…These key structural features common to both agonists and antagonists can therefore be ascribed to important, if not critical, binding interactions between these ligands and the AR. The key SAR findings are summarized below [25,27] 2) The amide and the tertiary carbinol were critical for activity in this series.…”